The Mechanism Of Par-4 In Islet β Cell Apoptosis In Type 2 Diabetes Mellitus

Part-1 Effect of Par-4 on apoptosis of islet β cells in type 2 diabetic miceObjective: Islet beta cell apoptosis plays an important role in islet cell dysfunction in type 2 diabetes mellitus.Par-4(apoptosis response-4 Prostate)is a pro-apoptotic factor which induces a variety of tumor cell apoptosis in previous research.However,it is not clear whether the Par-4/NF-kappa B is involved in the type 2 diabetes mellitus.Methods: small dose of STZ+ high-fat diet to construct the type 2 diabetic mouse models,and Par-4 expression was also knocked out in mouse.The mice were divided into 4 groups: normal group,diabetic group,normal +Par-4 knockout group,diabetic +Par-4 knockout group,we detected the nuclear expression of Par-4,NF-kappa B,islet β cell apoptosis and insulin secretion.Results: compared with normal group,the expression of par-4 and NF-κ B and apoptosis,insulin secretion ability had no significant change in normal+Par-4 knock out group,while in the diabetes group,Par-4 and NF-K B expression was significantly increased,the concentration of Par-4 and islet beta cell apoptosis were significantly increased,the ability of insulin secretion were decreased;Compared with the diabetic group,the expression of Par-4 and NF-kappa B,and the Par-4 concentration,islet β cell apoptosis were decreased,and insulin secretion ability was significantly increased in diabetic +Par-4 knockout group.Conclusion: type 2 diabetes can promote the secretion of Par-4 and the expression of Par-4 and NF-K B,which induced islet β cell apoptosis and dysfunction,knock-out of Par-4 in type 2 diabetic mouse decreased NF-kappa B expression and islet β cell apoptosis,improved the function of islet β cell.Part-2 The Mechanism of Par-4 in the apoptosis of islet β cells which induced by the glucoliptoxityObjective: Islet β cell apoptosis is primary pathogenic features of type 2 diabetes;Endoplasmic Reticulum(ER)stress and mitochondrial dysfunction are played an important role in this process.Previous researches indicated that Prostate apoptosis response-4(Par-4)/NF-κB induced cancer cell apoptosis via ER stress and mitochondrial dysfunction.However,both the involvement and exact mechanism of Par-4/NF-κB induces islet β cell apoptosis remains unknown.Methods: We used high glucose/palmitate intervention to mimic the Type 2 diabetes in vitro and the cultured NIT-1 cells were divided into six groups: the control group(Group C),the high glucose/palmitate intervention group(Group H),the over-expression in control group(Group C+Par-4),the down-regulation Par-4 in control group(Group C-Par-4),the over-expression of Par-4 in high glucose/palmitate intervention group(Group H+Par-4),and the down-regulation Par-4 in high glucose/palmitate intervention group(Group H-Par-4).We detected the protein expression of Par-4 and NF-κB and its activity of translation level,the apoptosis of the cells,the level of ER stress,the bio-marker of apoptosis pathway.Results: We demonstrated that the expression and secretion of Par-4 was increased by high glucose/palmitate intervention,it increased the expression and activation of NF-κB,which induced NIT-1 cell apoptosis,over-expression of Par-4 can aggregate these effects and down-expression of Par-4 attenuate these effects,and inhibition of NF-κB reduced the apoptosis induced by Par-4.Moreover,these effects were though the ER stress-cell membrane and mitochondrial pathway to induce apoptosis.Conclusion: Our findings reveal a novel role of Par-4/NF-κB in Islet β cell apoptosis and type 2 diabetes.